An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people.
Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases) and geographically localized, so that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. We conclude that because of rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.


Fast Volume Reconstruction From Motion Corrupted Stacks of 2D Slices.
Capturing an enclosing volume of moving subjects and organs using fast individual image slice acquisition has shown promise in dealing with motion artefacts. Motion between slice acquisitions results in spatial inconsistencies that can be resolved by slice-to-volume reconstruction (SVR) methods to provide high quality 3D image data. Existing algorithms are, however, typically very slow, specialised to specific applications and rely on approximations, which impedes their potential clinical use. In this paper, we present a fast multi-GPU accelerated framework for slice-to-volume reconstruction. It is based on optimised 2D/3D registration, super-resolution with automatic outlier rejection and an additional (optional) intensity bias correction. We introduce a novel and fully automatic procedure for selecting the image stack with least motion to serve as an initial registration target. We evaluate the proposed method using artificial motion corrupted phantom data as well as clinical data, including tracked freehand ultrasound of the liver and fetal Magnetic Resonance Imaging. We achieve speed-up factors greater than 30 compared to a single CPU system and greater than 10 compared to currently available state-of-the-art multi-core CPU methods. We ensure high reconstruction accuracy by exact computation of the point-spread function for every input data point, which has not previously been possible due to computational limitations. Our framework and its implementation is scalable for available computational infrastructures and tests show a speed-up factor of 1.70 for each additional GPU. This paves the way for the online application of image based reconstruction methods during clinical examinations. The source code for the proposed approach is publicly available.


Chemical composition and cytotoxicity of extracts of marjoram and rosemary and their activity against Sporothrix brasiliensis.
Motivated by increasing reports of antifungal resistance in human and animal sporotrichosis, this study evaluated the chemical composition, cytotoxicity and anti-Sporothrix brasiliensis activity of extracts of marjoram (Origanum majorana) and rosemary (Rosmarinus officinalis). Ten (INF10) and 60 min (INF60) infusions, a decoction and a hydroalcoholic extract (HAE, 70 %) were prepared from both plants (10 % w/v). The extract composition was analysed by liquid chromatography/mass spectrometry and the cytotoxicity was evaluated using a colorimetric assay in canine and feline kidney cells. Using a broth microdilution assay (CLSI M38-A2) adapted to the extracts, 30 Sporothrix brasiliensis isolates from dogs, cats and humans, and one Sporothrix schenckii were tested.Results/Key findings. The predominant phenolic compounds found in all extracts were 4-hydroxybenzoic acid, caffeic acid and chlorogenic acid. Luteolin was also one of the predominant compounds, but only in the HAE of marjoram. Extracts of marjoram maintained cell viability in concentrations up to 2.5 mg ml-1 for the feline cell line and up to 10 mg ml-1 for the canine cell line, whereas in rosemary, the cell viability for both kidney lines was maintained with concentrations up to 5 mg ml-1. The activity of rosemary extracts was low or absent. Among the marjoram extracts, HAE was highlighted and had fungistatic activity against Sporothrix brasiliensis (MIC5040 mg ml-1), including in all itraconazole-resistant isolates. S. schenckiisensu stricto was sensitive to marjoram extracts (MIC/MFC ≤5 mg ml-1), with the exception of INF10. These findings support the potential usefulness of the HAE of marjoram in the treatment of sporotrichosis.


Exercise for people with cancer: a systematic review.
This systematic review was completed by the Exercise for People with Cancer Guideline Development Group, a group organized by Cancer Care Ontario's Program in Evidence-Based Care (pebc). It provides background and guidance for clinicians with respect to exercise for people living with cancer in active and post treatment. It focuses on the benefits of specific types of exercise, pre-screening requirements for new referrals, safety concerns, and delivery models. Using the pebc's standardized approach, medline and embase were systematically searched for existing guidelines, systematic reviews, and primary literature. The search identified two guidelines, eighteen systematic reviews, and twenty-nine randomized controlled trials with relevance to the topic. The present review provides conclusions about the duration, frequency, and intensity of exercise appropriate for people living with cancer. The evidence shows that exercise is safe and provides benefit in quality of life and in muscular and aerobic fitness for people with cancer both during and after treatment. The evidence is sufficient to support the promotion of exercise for adults with cancer, and some evidence supports the promotion of exercise in group or supervised settings and for a long period of time to improve quality of life and muscular and aerobic fitness. Exercise at moderate intensities could also be sustainable for longer periods and could encourage exercise to be continued over an individual's lifetime. It is important that a pre-screening assessment be conducted to evaluate the effects of disease, treatments, and comorbidities.


The occurrence of Culicoides species, the vectors of arboviruses, at selected trap sites in Zimbabwe.
A study of the distribution of Culicoides species was conducted by establishing 12 light trap sites over five rainy seasons between 1998 and 2003 covering all the geo-climatic natural regions of Zimbabwe. In total, 279 919 specimens of Culicoides were trapped over a total of 163 trapping nights. The highest median counts of Culicoides per trapping night were recorded in natural region III, which has climatic conditions conducive to the successful development of the larvae. Culicoides imicola, the major vector of bluetongue and African horse sickness viruses in Africa, was found to be the most abundant species (80.4%), followed by Culicoides enderleini (5.9%) and Culicoides milnei (5.2%). This study identified 10 species of Culicoides that had not been previously described in Zimbabwe, including Culicoides loxodontis and Culicoides miombo, which are members of the C. imicola complex. A total of 23 994 Culicoides midges were collected from five trap sites in Harare, Zimbabwe, with the dominant species, C. imicola, representing 91.6% of the total collection. Seventeen arboviruses were isolated from these midges, 15 of which were bluetongue virus. The predominant bluetongue virus serotype was serotype 11, followed by serotypes 1, 8, 12 and 15. Bluetongue virus serotypes 1, 2, 8, 10, 12, 15, 16 and 18, detected in this study, had not been previously reported in Zimbabwe.


Distinct roles of deiodinases on the phenotype of Mct8 defect: a comparison of eight different mouse genotypes.
Mice deficient in the thyroid hormone (TH) transporter Mct8 (Mct8KO) have increased 5'-deiodination and impaired TH secretion and excretion. These and other unknown mechanisms result in the low-serum T(4), high T(3), and low rT(3) levels characteristic of Mct8 defects. We investigated to what extent each of the 5'-deiodinases (D1, D2) contributes to the serum TH abnormalities of the Mct8KO by generating mice with all combinations of Mct8 and D1 and/or D2 deficiencies and comparing the resulting eight genotypes. Adding D1 deficiency to that of Mct8 corrected the serum TH abnormalities of Mct8KO mice, normalized brain T(3) content, and reduced the impaired expression of TH-responsive genes. In contrast, Mct8D2KO mice maintained the serum TH abnormalities of Mct8KO mice. However, the serum TSH level increased 27-fold, suggesting a severely impaired hypothalamo-pituitary-thyroid axis. The brain of Mct8D2KO manifested a pattern of more severe impairment of TH action than Mct8KO alone. In triple Mct8D1D2KO mice, the markedly increased serum TH levels produced milder brain defect than that of Mct8D2KO at the expense of more severe liver thyrotoxicosis. Additionally, we observed that mice deficient in D2 had an unexplained marked reduction in the thyroid growth response to TSH. Our studies on these eight genotypes provide a unique insight into the complex interplay of the deiodinases in the Mct8 defect and suggest that D1 contributes to the increased serum T(3) in Mct8 deficiency, whereas D2 mainly functions locally, converting T(4) to T(3) to compensate for distinct cellular TH depletion in Mct8KO mice.


Depressive symptoms after a sexual assault among women: understanding victim-perpetrator relationships and the role of social perceptions.
Although mental health impact of gender based violence has been documented for many decades, the impact of the socio-cultural dimensions and type of perpetrator on mental health outcomes has not been described outside of developed countries. We explore depression symptomatology four to six weeks post-rape in South Africa and examine whether this differs according to the circumstances of the rape. 140 participants recruited from public hospital services in the Eastern and Western Cape provinces were interviewed within two weeks after completing the post exposure prophylaxis (PEP) medication. A structured questionnaire was used to collect data on socio-demographic and sexual assault characteristics including perpetrator. Depressive symptomatology was measured using the Centre for Epidemiological Studies Depression Scale. 84.3% (95% CI: 78.1-90.3) women were found to have high levels of depressive symptoms, but lower levels were found among women raped in circumstances in which there was a lesser likelihood of blame such as those raped by strangers rather than intimate partners (Odds Ratio: (OR) 0.28 (95% Confidence Intervals (CI): 0.11-0.69) and higher levels were associated with experiencing four or more side effects related to PEP medication (OR: 3.79: CI: 1.03-13.94). Receiving support and severe sexual assaults (involving weapons and multiple perpetrators) were not associated with depression. The study does not support the general assumption that more violent rape causes more psychological harm. These results have important implications for individual treatment because it is more generally assumed that multiple perpetrator rapes, stranger rapes and those with weapons would result in more psychological trauma and thus more enduring symptoms. Our findings point to the importance of understanding the socio-cultural dimensions, including dynamics of blame and stigma, of rape on mental health sequelae.


An ABC transporter and a cytochrome P450 of Nectria haematococca MPVI are virulence factors on pea and are the major tolerance mechanisms to the phytoalexin pisatin.
The fungal plant pathogen Nectria haematococca MPVI produces a cytochrome P450 that is responsible for detoxifying the phytoalexin pisatin, produced as a defense mechanism by its host, garden pea. In this study, we demonstrate that this fungus also produces a specific ATP-binding cassette (ABC) transporter, NhABC1, that enhances its tolerance to pisatin. In addition, although both mechanisms individually contribute to the tolerance of pisatin and act as host-specific virulence factors, mutations in both genes render the fungus even more sensitive to pisatin and essentially nonpathogenic on pea. NhABC1 is rapidly induced after treatment with pisatin in vitro and during infection of pea plants. Furthermore, NhABC1 was able to confer tolerance to the phytoalexin rishitin, produced by potato. NhABC1 appears to be orthologous to GpABC1 of the potato pathogen Gibberella pulicaris and, along with MoABC1 from Magnaporthe oryzae, resides in a phylogenetically related clade enriched with ABC transorters involved in virulence. We propose that NhABC1 and the cytochrome P450 may function in a sequential manner in which the energy expense from pisatin efflux by NhABC1 releases the repression of the cytochrome P450, ultimately allowing pisatin tolerance by two mechanisms. These results demonstrate that a successful pathogen has evolved multiple mechanisms to overcome these plant antimicrobial compounds.


The Importance of Maize Management on Dung Beetle Communities in Atlantic Forest Fragments.
Dung beetle community structures changes due to the effects of destruction, fragmentation, isolation and decrease in tropical forest area, and therefore are considered ecological indicators. In order to assess the influence of type of maize cultivated and associated maize management on dung beetle communities in Atlantic Forest fragments surrounded by conventional and transgenic maize were evaluated 40 Atlantic Forest fragments of different sizes, 20 surrounded by GM maize and 20 surrounded by conventional maize, in February 2013 and 2014 in Southern Brazil. After applying a sampling protocol in each fragment (10 pitfall traps baited with human feces or carrion exposed for 48 h), a total of 3454 individuals from 44 species were captured: 1142 individuals from 38 species in GM maize surrounded fragments, and 2312 from 42 species in conventional maize surrounded fragments. Differences in dung beetle communities were found between GM and conventional maize communities. As expected for fragmented areas, the covariance analysis showed a greater species richness in larger fragments under both conditions; however species richness was greater in fragments surrounded by conventional maize. Dung beetle structure in the forest fragments was explained by environmental variables, fragment area, spatial distance and also type of maize (transgenic or conventional) associated with maize management techniques. In Southern Brazil's scenario, the use of GM maize combined with associated agricultural management may be accelerating the loss of diversity in Atlantic Forest areas, and consequently, important ecosystem services provided by dung beetles may be lost.


Oxytocin signaling in the medial amygdala is required for sex discrimination of social cues.
The neural control of social behaviors in rodents requires the encoding of pheromonal cues by the vomeronasal system. Here we show that the typical preference of male mice for females is eliminated in mutants lacking oxytocin, a neuropeptide modulating social behaviors in many species. Ablation of the oxytocin receptor in aromatase-expressing neurons of the medial amygdala (MeA) fully recapitulates the elimination of female preference in males. Further, single-unit recording in the MeA uncovered significant changes in the sensory representation of conspecific cues in the absence of oxytocin signaling. Finally, acute manipulation of oxytocin signaling in adults is sufficient to alter social interaction preferences in males as well as responses of MeA neurons to chemosensory cues. These results uncover the critical role of oxytocin signaling in a molecularly defined neuronal population in order to modulate the behavioral and physiological responses of male mice to females on a moment-to-moment basis.


Reclassification of non-type strain Clostridium pasteurianum NRRL B-598 as Clostridium beijerinckii NRRL B-598.
The complete genome sequence of non-type strain Clostridium pasteurianum NRRL B-598 was introduced last year; it is an oxygen tolerant, spore-forming, mesophilic heterofermentative bacterium with high hydrogen production and acetone-butanol fermentation ability. The basic genome statistics have shown its similarity to C. beijerinckii rather than the C. pasteurianum species. Here, we present a comparative analysis of the strain with several other complete clostridial genome sequences. Besides a 16S rRNA gene sequence comparison, digital DNA-DNA hybridization (dDDH) and phylogenomic analysis confirmed an inaccuracy of the taxonomic status of strain Clostridium pasteurianum NRRL B-598. Therefore, we suggest its reclassification to be Clostridium beijerinckii NRRL B-598. This is a specific strain and is not identical to other C. beijerinckii strains. This misclassification explains its unexpected behavior, different from other C. pasteurianum strains; it also permits better understanding of the bacterium for a future genetic manipulation that might increase its biofuel production potential.


[Investigation into the effect of household triatomine infestation on awareness among inhabitants of settlements and re-settlements in areas infested with Triatoma sordida in São Paulo State, Brazil].
This study aims to analyze the effect of domiciliary infestation by triatomine bugs on the degree to which inhabitants are aware of potential vector transmission of Chagas disease. Such recently constructed dwellings comprise housing groups classified as settlements and re-settlements, selected respectively in the municipalities of Euclides da Cunha Paulista and Paulicéia, São Paulo State, Brazil. Both municipalities are under the jurisdiction of the Presidente Prudente Health Administrative Region. Of the 319 residents, some 100 (76.0% of whom were re-settlement residents) knew about triatomine bugs. Housing units infested with triatomines were inhabited by 93 people. In 79.2% of the infested houses, 26.8% of the residents knew about Chagas disease and its vectors, but in 50.0% of the households, some people did not know what to do in case of triatomine infestation. Population samples from settlements and re-settlements, regardless of sex, age, and the State of origin, showed no difference in attitudes towards the prevention of Chagas disease or knowledge of the disease vector.


Analysis of hereditary angioedema attacks requiring a second dose of ecallantide.
Effective treatment of acute attacks is critical in managing hereditary angioedema (HAE). Ecallantide, a plasma kallikrein inhibitor, is approved for the treatment of HAE attacks. Occasionally, a second dose is needed when treating attacks of HAE. To evaluate the characteristics of HAE attacks requiring a second dose (dose B) of ecallantide. Data from all ecallantide clinical trials (EDEMA2, EDEMA4, and DX-88/19) that allowed an open-label dose B were included in this analysis. Patient and attack characteristics potentially predictive of dose B after ecallantide were analyzed by logistic regression. A multivariate model was built using a backward selection process, incorporating variables from the univariate model with P < .20 and removing factors with the highest P value until only significant (P < .05) factors remained. The analysis included 732 ecallantide-treated HAE attacks in 179 patients. Dose B was required in 88 attacks (12.0%), most (80.5%) for incomplete response. By attack location, 31 of 325 abdominal attacks (9.5%), 17 of 158 laryngeal attacks (10.8%), and 40 of 242 peripheral attacks (16.5%) required dose B. On the basis of the univariate analysis, baseline severity (odds ratio = 1.33, P = .15) and peripheral attack (odds ratio = 1.80, P = .01) were identified as potential predictive factors; abdominal attacks had an inverse correlation (odds ratio = 0.64, P = .055). However, the multivariate analysis identified only peripheral attacks as statistically significantly correlated (P < .05) with dose B requirement. A single, 30-mg dose of ecallantide was effective for most HAE attacks (88.0%). Patients with peripheral attacks of HAE were more likely to require a second dose of ecallantide after 4 hours. clinicaltrials.gov Identifiers: not applicable for EDEMA2 (trial was conducted before registration requirements were implemented), NCT00457015 for EDEMA4, and NCT00456508 for DX-88/19.


Chromosomal localisation of the human homologues to the oncogenes erbA and B.
Avian erythroblastosis virus (AEV) induces acute erythroleukemia and sarcomas in vivo and it transforms erythroblasts and fibroblasts in vitro. The virus has two host cell-derived genes, v-erbA and v-erbB. The latter encodes the oncogenic capacity of the virus, whereas v-erbA enhances the erythroblast transforming effects of v-erbB while being unable to induce neoplasms independently. Recently, human cellular homologues of these viral erb genes have been isolated. The chromosomal locations of two of these genes have been determined using EcoRI-digested DNA prepared from human-mouse somatic cell hybrids. The human c-erbA1 gene has been assigned to chromosome 17 and is located between 17p11 and 17q21. The human c-erbB sequence has been assigned to chromosome 7 and is located between 7pter and 7q22. Thus, in the human genome these genes are on two separate chromosomes. No evidence for the involvement of the human c-erb genes in neoplasia has been found.


Water-structuring molecules and nanomaterials enhance radiofrequency heating in biologically relevant solutions.
For potential applications in nano-mediated radiofrequency cancer hyperthermia, the nanomaterial under investigation must increase the heating of any aqueous solution in which it is suspended when exposed to radiofrequency electric fields. This should also be true for a broad range of solution conductivities, especially those that artificially mimic the ionic environment of biological systems. Herein we demonstrate enhanced heating of biologically relevant aqueous solutions using kosmotropes and a hexamalonoserinolamide fullerene.


Delay in diabetic retinopathy screening increases the rate of detection of referable diabetic retinopathy.
To assess whether there is a relationship between delay in retinopathy screening after diagnosis of type 2 diabetes and level of retinopathy detected. Patients were referred from 88 primary care practices to an English National Health Service diabetic eye screening programme. Data for screened patients were extracted from the primary care databases using semi-automated data collection algorithms supplemented by validation processes. The programme uses two-field mydriatic digital photographs graded by a quality assured team. Data were available for 8183 screened patients with diabetes newly diagnosed in 2005, 2006 or 2007. Only 163 with type 1 diabetes were identified and were insufficient for analysis. Data were available for 8020 with newly diagnosed type 2 diabetes. Of these, 3569 were screened within 6 months, 2361 between 6 and 11 months, 1058 between 12 and 17 months, 366 between 18 and 23 months, 428 between 24 and 35 months, and 238 at 3 years or more after diagnosis. There were 5416 (67.5%) graded with no retinopathy, 1629 (20.3%) with background retinopathy in one eye, 753 (9.4%) with background retinopathy in both eyes and 222 (2.8%) had referable diabetic retinopathy. There was a significant trend (P = 0.0004) relating time from diagnosis to screening detecting worsening retinopathy. Of those screened within 6 months of diagnosis, 2.3% had referable retinopathy and, 3 years or more after diagnosis, 4.2% had referable retinopathy. The rate of detection of referable diabetic retinopathy is elevated in those who were not screened promptly after diagnosis of type 2 diabetes.


Toxic effects of IV iron preparations in CKD patients.
Loss of blood associated with hemodialysis procedures and laboratory testing, together with impaired iron absorption due to elevation of hepcidin, invariably cause iron deficiency in end-stage renal disease patients. For this reason, nearly all ESRD patients require intravenous iron to replete iron stores. Unfortunately, intravenously administered iron is often used routinely with inadequate attention to the body iron stores or severity of systemic inflammation. This has led to an epidemic of iron overload in the ESRD population. Only a minute amount (3-4 mg) of the total body iron (3-4 g in an adult man) resides in the plasma bound to transferrin, which serves as a safe vehicle for iron transport in the circulation. IV iron products are generally administered as bolus injections of 100 to 1000 mg, which far exceeds the available pool of free transferrin and represents a huge quantity compared to the intestinal iron absorption of 1 to 2 mg/day in the course of 3 to 4 meals. Administration of these products results in an increased plasma level of catalytically active non-transferrin bound iron and the rise in the biomarkers of oxidative stress and inflammation. IV iron bypasses the biological safeguards for the transport and handling of iron and helps to intensify chronic kidney disease-associated oxidative stress and inflammation. As briefly described in this review, indiscriminate use of IV iron can accelerate cardiovascular disease, promote microbial infections, aggravate viral hepatitis, and worsen diabetes and diabetic complications in such patients. For these reasons IV iron should be used judiciously in this vulnerable population.


Determinants of European parents' decision on the vaccination of their children against measles, mumps and rubella: A systematic review and meta-analysis.
Low measles, mumps and rubella (MMR) immunization levels in European children highlight the importance of identifying determinants of parental vaccine uptake to implement policies for increasing vaccine compliance. The aim of this paper is to identify the main factors associated with partial and full MMR vaccination uptake in European parents, and combine the different studies to obtain overall quantitative measures. This activity is included within the ESCULAPIO project, funded by the Italian Ministry of Health. ORs and CIs were extracted, sources of heterogeneity explored and publication bias assessed. Forty-five papers were retrieved for the qualitative study, 26 of which were included in the meta-analysis. The following factors were associated with lower MMR vaccine uptake: misleading knowledge, beliefs and perceptions on vaccines (OR 0.57, CI 0.37-0.87); negative attitudes and behaviors toward vaccination (OR 0.71, CI 0.52-0.98); demographic characteristics, such as different ethnicity in Southern populations (OR 0.44, CI 0.31-0.61), higher child's age (OR 0.80, CI 0.76-0.85); low socio-economic status (OR 0.64, CI 0.51-0.80), especially low income (OR 0.39, CI 0.25-0.60) and education (OR 0.64, CI 0.48-0.84), high number of children (OR 0.54, CI 0.42-0.69), irregular marital status (OR 0.80, CI 0.66-0.96). The factors explaining heterogeneity were country location, administration modality, collection setting and responses reported on MMR alone or in combination. Findings from this study suggest policy makers to focus communication strategies on providing better knowledge, correct beliefs and perceptions on vaccines, and improving attitudes and behaviors in parents; and to target policies to people of ethnic minority from Southern Europe, low educated and deprived, with higher number of children and non-married marital status.


HmtDB 2016: data update, a better performing query system and human mitochondrial DNA haplogroup predictor.
The HmtDB resource hosts a database of human mitochondrial genome sequences from individuals with healthy and disease phenotypes. The database is intended to support both population geneticists as well as clinicians undertaking the task to assess the pathogenicity of specific mtDNA mutations. The wide application of next-generation sequencing (NGS) has provided an enormous volume of high-resolution data at a low price, increasing the availability of human mitochondrial sequencing data, which called for a cogent and significant expansion of HmtDB data content that has more than tripled in the current release. We here describe additional novel features, including: (i) a complete, user-friendly restyling of the web interface, (ii) links to the command-line stand-alone and web versions of the MToolBox package, an up-to-date tool to reconstruct and analyze human mitochondrial DNA from NGS data and (iii) the implementation of the Reconstructed Sapiens Reference Sequence (RSRS) as mitochondrial reference sequence. The overall update renders HmtDB an even more handy and useful resource as it enables a more rapid data access, processing and analysis. HmtDB is accessible at http://www.hmtdb.uniba.it/.


Paleoamerican diet, migration and morphology in Brazil: archaeological complexity of the earliest Americans.
During the early Holocene two main paleoamerican cultures thrived in Brazil: the Tradição Nordeste in the semi-desertic Sertão and the Tradição Itaparica in the high plains of the Planalto Central. Here we report on paleodietary singals of a Paleoamerican found in a third Brazilian ecological setting--a riverine shellmound, or sambaqui, located in the Atlantic forest. Most sambaquis are found along the coast. The peoples associated with them subsisted on marine resources. We are reporting a different situation from the oldest recorded riverine sambaqui, called Capelinha. Capelinha is a relatively small sambaqui established along a river 60 km from the Atlantic Ocean coast. It contained the well-preserved remains of a Paleoamerican known as Luzio dated to 9,945±235 years ago; the oldest sambaqui dweller so far. Luzio's bones were remarkably well preserved and allowed for stable isotopic analysis of diet. Although artifacts found at this riverine site show connections with the Atlantic coast, we show that he represents a population that was dependent on inland resources as opposed to marine coastal resources. After comparing Luzio's paleodietary data with that of other extant and prehistoric groups, we discuss where his group could have come from, if terrestrial diet persisted in riverine sambaquis and how Luzio fits within the discussion of the replacement of paleamerican by amerindian morphology. This study adds to the evidence that shows a greater complexity in the prehistory of the colonization of and the adaptations to the New World.


A Hospital-Wide Intervention to Improve Compliance With TNM Cancer Staging Documentation.
Accurate oncologic staging meeting clinical practice guidelines is essential for guideline adherence, quality assessment, and survival outcomes. However, timely and uniform documentation in the electronic health record (EHR) at the time of diagnosis is a challenge for providers. This quality improvement project aimed to increase provider compliance of timely clinical TNM (cTNM) or pathologic TNM (pTNM) staging for newly diagnosed oncologic patients. Providers in the following site-specific oncologic teams were included: head and neck, skin, breast, genitourinary, gastrointestinal, lung and thoracic, gynecologic, colorectal, and bone marrow transplant. Interventions to facilitate timely cTNM and pTNM staging included standardized EHR-based workflows, learning modules, stakeholder meetings, and individualized provider training sessions. For most teams, staging was considered compliant if it was completed in the EHR within the first 7 days of the calendar month after the date of the patient visit. Factors associated with staging compliance were analyzed using logistic regression models. From January 1, 2014, to December 31, 2018, 7,787 preintervention and 5,152 postintervention new patient visits occurred. During the preintervention period, staging was compliant in 5.6% of patients compared with 67.4% of patients after intervention (P<.001). In the final month of the postintervention period, the overall staging compliance rate was 78.1%. At most recent tracking, staging compliance was 95%, 97%, and 93% in December 2019, January 2020, and February 2020, respectively. Logistic regression found that increasing years of provider experience was associated with decreased staging compliance. High rates of staging compliance in complex multidisciplinary academic oncologic practice models can be achieved via comprehensive quality improvement and structured initiatives. This approach serves as a model for improving oncologic documentation systems to facilitate clinical decision-making and multidisciplinary coordination of care.


Theaflavins suppress tumor growth and metastasis via the blockage of the STAT3 pathway in hepatocellular carcinoma.
Theaflavins, the major black tea polyphenols, have been reported to exhibit promising antitumor activities in several human cancers. However, the role of theaflavins in hepatocellular carcinoma (HCC) is still unknown. In this study, we found that theaflavins could significantly inhibit proliferation, migration, and invasion, and induce apoptosis in HCC cells in vitro. Furthermore, we found that theaflavins inhibited the growth and metastasis of HCC in an orthotopic model and a lung metastasis model. Immunohistochemical analyses and terminal deoxynucleotidyl transferase dUTP nick end-labeling assays showed that theaflavins could suppress proliferation and induce apoptosis in vivo. Theaflavins also suppressed constitutive and inducible signal transducer and activator of transcription 3 (STAT3) phosphorylation. The downstream proteins regulated by STAT3, including the antiapoptotic proteins (Bcl-2 and Survivin) and the invasion-related proteins (MMP-2, MMP-9), were also downregulated after theaflavins treatment. Theaflavins induced apoptosis by activating the caspase pathway. Together, our results suggest that theaflavins suppress the growth and metastasis of human HCC through the blockage of the STAT3 pathway, and thus may act as potential therapeutic agents for HCC.


Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas.
This guideline provides recommendations for the use of PET imaging in gliomas. The review examines established clinical benefit in glioma patients of PET using glucose ((18)F-FDG) and amino acid tracers ((11)C-MET, (18)F-FET, and (18)F-FDOPA). An increasing number of studies have been published on PET imaging in the setting of diagnosis, biopsy, and resection as well radiotherapy planning, treatment monitoring, and response assessment. Recommendations are based on evidence generated from studies which validated PET findings by histology or clinical course. This guideline emphasizes the clinical value of PET imaging with superiority of amino acid PET over glucose PET and provides a framework for the use of PET to assist in the management of patients with gliomas.


Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members.
We examined the role of hepatic heparan sulfate in triglyceride-rich lipoprotein metabolism by inactivating the biosynthetic gene GlcNAc N-deacetylase/N-sulfotransferase 1 (Ndst1) in hepatocytes using the Cre-loxP system, which resulted in an approximately 50% reduction in sulfation of liver heparan sulfate. Mice were viable and healthy, but they accumulated triglyceride-rich lipoprotein particles containing apoB-100, apoB-48, apoE, and apoCI-IV. Compounding the mutation with LDL receptor deficiency caused enhanced accumulation of both cholesterol- and triglyceride-rich particles compared with mice lacking only LDL receptors, suggesting that heparan sulfate participates in the clearance of cholesterol-rich lipoproteins as well. Mutant mice synthesized VLDL normally but showed reduced plasma clearance of human VLDL and a corresponding reduction in hepatic VLDL uptake. Retinyl ester excursion studies revealed that clearance of intestinally derived lipoproteins also depended on hepatocyte heparan sulfate. These findings show that under normal physiological conditions, hepatic heparan sulfate proteoglycans play a crucial role in the clearance of both intestinally derived and hepatic lipoprotein particles.


Pathogenesis of columnar-lined esophagus.
Since its initial description, the pathogenesis of the columnar-lined esophagus (CLE) has been surrounded by many controversies. The first controversy is related to the existence of the condition itself. The second controversy centers on whether the CLE is a congenital or an acquired condition. In this article, we review the congenital and acquired theories of development of CLE and discuss the various factors in acquisition of CLE. The bulk of evidence in the literature suggests that CLE is an acquired condition.


Specular scattering by preferentially oriented ice crystals.
Scattered light for preferentially oriented ice crystals is divided into specular and diffuse components, where the specular scattering is created by horizontally oriented facets of fluttering crystals. The specular component for a fluttering thin plate modeling these crystals is found analytically. The solution obtained is a two-dimensional (2D) convolution of a geometric optics pattern depending only on flutter and an independent diffraction function. The geometric optics pattern is explicitly expressed through the probability density for particle tilts, and the diffraction function is taken in the Fraunhofer diffraction approximation. The 2D convolution calculated numerically reveals a cumulative enhancement of scattered light in the scattering domain center. Certain possibilities to retrieve both flutter parameters and particle sizes from the specular patterns are discussed.


First Report of Powdery Mildew on Flamboyant Tree Caused by Erysiphe quercicola in Brazil.
Flamboyant (Delonix regia) is an ornamental tree that is native to Madagascar and frequently used in gardens and parks worldwide. Powdery mildew was observed on flamboyant plants in the cities of Piracicaba and São Carlos (State of São Paulo, Brazil) during the springs of 2010 and 2011. All sampled plants (~15 plants) were affected by the disease. Affected plants had abundant, white powdery masses of conidia and mycelium on floral buds that is typical of powdery mildew, but these structures were not observed on leaves and petioles. Diseased buds were observed at all developmental stages. The fungus was identified as Erysiphe quercicola on the basis of scanning electron microscopy, light microscopy, and sequence analysis of the internal transcribed spacer (ITS) region. Conidia were produced in short chains of four to five spores on erect conidiophores. Conidiophores were unbranched, cylindrical, 50 to 80 μm long (mean 68.8 ± 10.8 μm), composed of a cylindrical foot cell 25 to 40 μm long (mean 32.2 ± 4.9 μm), and one to two shorter cells. Conidia were ellipsoid-ovoid to subcylindrical, 22 to 37 μm long (mean 30.9 ± 4.4 μm), and 10 to 18 μm wide (mean 15.1 ± 2.8 μm). Germ tubes were produced apically and ended in a lobed appressorium. Colonizing hyphae also had a well-developed lobed appressorium. Chasmothecia were not observed on buds. DNA was extracted from conidia, conidiophores, and mycelium and used to amplify the ITS (ITS1-5.8s-ITS2) region using the ITS1 and ITS4 primers (2) and its sequence (612 nt) was deposited under Accession No. JQ034229 in the GenBank. Searches with the BLASTn algorithm revealed 100% similarity with E. quercicola from oak (Accession Nos. AB292693.1, AB292691.1, and AB292690.1) (1). To fulfill Koch's postulates, 10 detached young floral buds, 0.4 to 0.8 cm in diameter, were inoculated with five to eight conidia collected on floral buds using an eyelash brush. Inoculated buds were placed on moistened filter paper in petri dishes. The negative control consisted of noninoculated young floral buds. Inoculated and noninoculated buds were incubated in a growth chamber at 25°C and a 12-h photoperiod. Powdery mildew structures were observed 6 to 8 days after inoculation. To our knowledge, E. quercicola has not been reported previously as a pathogen of flamboyant tree since there is no record in the Erysipahales database ( http://erysiphales.wsu.edu/ ). Although the economic impact of the disease is limited, its incidence might induce the abortion of floral buds and accelerate the senescence of flowers, thus reducing the aesthetic value of the trees. References: (1) S. Takamatsu et al. Mycol Res. 111:809, 2007. (2) T. J. White et al. PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, 1990.


Cryo-EM model of the bullet-shaped vesicular stomatitis virus.
Vesicular stomatitis virus (VSV) is a bullet-shaped rhabdovirus and a model system of negative-strand RNA viruses. Through direct visualization by means of cryo-electron microscopy, we show that each virion contains two nested, left-handed helices: an outer helix of matrix protein M and an inner helix of nucleoprotein N and RNA. M has a hub domain with four contact sites that link to neighboring M and N subunits, providing rigidity by clamping adjacent turns of the nucleocapsid. Side-by-side interactions between neighboring N subunits are critical for the nucleocapsid to form a bullet shape, and structure-based mutagenesis results support this description. Together, our data suggest a mechanism of VSV assembly in which the nucleocapsid spirals from the tip to become the helical trunk, both subsequently framed and rigidified by the M layer.


Thrombus formation: direct real-time observation and digital analysis of thrombus assembly in a living mouse by confocal and widefield intravital microscopy.
We have developed novel instrumentation using confocal and widefield microscopy to image and analyze thrombus formation in real time in the microcirculation of a living mouse. This system provides high-speed, near-simultaneous acquisition of images of multiple fluorescent probes and a brightfield channel, and supports laser-induced injury through the microscope optics. Although this imaging facility requires interface of multiple hardware components, the primary challenge in vascular imaging is careful experimental design and interpretation. This system has been used to localize tissue factor during thrombus formation, to observe defects in thrombus assembly in genetically altered mice, to study the kinetics of platelet activation and P-selectin expression following vascular injury, to analyze leukocyte rolling on arterial thrombi, to generate three-dimensional models of thrombi, and to analyze the effect of antithrombotic agents in vivo.


High-intensity interval training programme for obese youth (HIP4YOUTH): A pilot feasibility study.
Recently, there has been growing interest in high-intensity interval training (HIT) as a strategy to improve health. In this pilot study, we examined the feasibility of a 4-week low-volume HIT and its effects on cardiorespiratory fitness (CRF), blood pressure (BP) and enjoyment in overweight and obese youth. Twelve adolescents (body mass index (BMI): 34.8 ± 3.9 kg · m‒2, 14.9 ± 1.5 years) participated in 12 sessions of HIT (10 × 60 s cycling bouts eliciting ~90% maximal heart rate, interspersed with 90 s recovery, 30 min/session, 3 sessions/week) over ~4 weeks. All the participants completed the study and exercise attendance averaged 92%. Despite no changes in body weight and total fat, HIT resulted in significant (P < 0.01) increases in CRF (pre: 20.1 versus post: 22.2 ml · kg‒1 · min‒1) and exercise time (pre: 425 versus post: 509 s) during peak oxygen uptake test, and a reduction in resting systolic BP (pre: 115.8 versus post: 107.6 mmHg). The majority of study participants (83%) enjoyed HIT and more than half of the participants (58%) reported that HIT is a more enjoyable form of exercise compared to other types of exercises. Low-volume HIT is a useful strategy to promote exercise participation and improve cardiovascular health in overweight and obese youth.


First Report of Asian Brown Rot Caused by Monilia polystroma on Apricot in Switzerland.
A survey for Monilia fructicola (G. Winter) Honey on apricots (Prunus armeniaca L.) was conducted in July and August 2009 and 2010 in Canton Wallis, Switzerland. Mummies of fruits showing brown rot were collected and isolations were conducted. Nearly 200 fungal isolates, tentatively identified as M. fructigena, were retested with a multiplex PCR (1). With the Agilent 2100 Bioanalyzer (Agilent Technologies, Basel, Switzerland) instead of 1.5% agarose gels, the 23 bp difference between the diagnostic fragments of M. fructigena and M. polystroma van Leeuwen (1) could clearly be scored. M. polystroma was diagnosed in 3 of 65 and 1 of 132 isolates collected in 2009 (13 orchards) and 2010 (10 orchards), respectively. The internal transcribed spacer (ITS) regions of four isolates (09-G4, 09-P16, 09-S5, and 10-C6) were amplified and sequenced (4). The four sequences (GenBank No. JN128835) as well as those of the Hungarian isolate UFT (AM937114 [3]) were identical and highly similar to the type sequence for M. polystroma (Y17876 [2]). The type sequence had a "T" at position 414, which was lacking in the other five sequences. The genomic region of unknown function used by Côté et al. (1) to develop their PCR diagnostic tool was sequenced for isolate 09-G4 with primers MFG.for (3) and M Poly rev 5'-CCACTTACATTTTTGGCTATTG-3'. The Swiss isolate (GenBank No. JN128836) and the Hungarian isolate UFT (AM937120) sequences were identical. The pathogenicity of isolate 09-G4 was tested on Golden delicious apples. Six apples were surface sterilized (70% ethanol), halved, and placed in sterile plastic boxes cut-side down. Further, six half apples were wounded in the center with a round scalpel with a diameter of 1 cm and inoculated with a round, potato dextrose agar (PDA) plug (1-cm diameter) of actively growing mycelium (5- to 7-day-old culture). Control apples (six halves) were treated with a PDA plug without mycelium. All fruits were incubated at 20°C with a 12-h light 12-h dark cycle. Seven days after inoculation, typical brown rot symptoms were visible on all inoculated fruits. Mock inoculated fruits remained healthy. Three inoculated halves, in addition to the brown rot symptoms, also produced sporodochia and around the inoculation point the tissue become black. With the multiplex PCR (1), M. polystroma was identified as the pathogen causing brown rot symptoms on the inoculated apples. The ellipsoid single-cell hyaline conidia of isolate 09-G4 grown on the Golden delicious apples averaged 15.2 ± 4.0 × 8.97 ± 1.1 μm and were the expected size for M. polystroma conidia (14.9 to 9.1 μm [4]). The first evidence of a new Monilia species was reported by Fulton et al. (2). They found that M. fructigena isolates from Japan were distinguishable from European isolates by five base substitutions in the ITS region (four in ITS1 and one in ITS2). Later, van Leeuwen et al. (4) found that the two groups of isolates could also be distinguished by morphological differences and described the new species as M. polystroma. According to the Centre for Agricultural Bioscience International, the impact of M. polystroma in a new area is presumed to be the same or very similar to that of M. fructigena. To our knowledge, this is the first report of M. polystroma in Swiss orchards. References: (1) M.-J. Côté et al. Plant Dis. 88:1219, 2004. (2) C. E. Fulton et al. Eur. J. Plant Pathol. 105:495, 1999. (3) M. Petróczy and L. Palkovics. Eur. J. Plant Pathol. 125:343, 2009. (4) G. C. M. van Leeuwen et al. Mycol. Res. 106:444, 2002.


Technology-Based Interventions for Nursing Home Residents: Implications for Nursing Home Practice Amid and Beyond the Influence of COVID-19: A Systematic Review Protocol.
A growing number of technology-based interventions are used to support the health and quality of life of nursing home residents. The onset of COVID-19 and recommended social distancing policies that followed led to an increased interest in technology-based solutions to provide healthcare and promote health. Yet, there are no comprehensive resources on technology-based healthcare solutions that describe their efficacy for nursing home residents. This systematic review will identify technology-based interventions designed for nursing home residents and describe the characteristics and effects of these interventions concerning the distinctive traits of nursing home residents and nursing facilities. Additionally, this paper will present practical insights into the varying intervention approaches that can assist in the delivery of broad digital health solutions for nursing home residents amid and beyond the impact of COVID-19. Databases including PubMed, PsycINFO, CINAHL, and Scopus will be used to identify articles related to technology-based interventions for nursing home residents published between January 1st, 2010 to December 4th, 2020. Titles, abstracts, and full-texts papers will be reviewed against the eligibility criteria. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses procedures will be followed for the reporting process, and implications for existing interventions and research evaluated by a multidisciplinary research team. NA-protocol study. Our study will fill critical gaps in the literature by providing a review of technology-based interventions tested in the nursing home setting. As the older adult population grows, there is an urgent need to identify effective technology-based interventions that can address the distinctive characteristics and preferences of nursing home residents. Clear and comprehensive understanding of how available technology-based health solutions facilitate healthcare for nursing home residents will shed light on the approaches open to residents to fend off the negative health consequences amid and beyond the influence of COVID-19. PROSPERO CRD 42020191880.


The effect of latent adenovirus 5 infection on cigarette smoke-induced lung inflammation.
The aim of this study was to test the hypothesis that latent adenovirus (Ad) 5 infection increases the lung inflammation that follows a single acute exposure to cigarette smoke. A recently developed model of latent adenoviral infection in guinea-pigs was used. Twelve animals were infected with Ad5 (10(8) plaque-forming units) and 12 animals were sham-infected. Thirty five days later six Ad5-infected and six sham-infected animals were exposed to the smoke from five cigarettes. The remaining animals were used as controls for both infection and smoking. As markers of inflammation, the volume fraction of macrophages, T-lymphocytes, neutrophils and eosinophils were measured by quantitative histology. We found that latent Ad5-infection alone, doubled the number of macrophages in the lung parenchyma and that smoking alone, doubled the volume fraction of neutrophils in the airway wall and the volume fraction of macrophages in the lung parenchyma. Neither viral infection nor smoking, alone, had an effect on T-lymphocytes or eosinophils. However, the combination of viral infection and smoking doubled the T-lymphocyte helper cells and quadrupled the volume fraction of macrophages in the lung parenchyma. We conclude that in guinea-pigs, latent adenovirus 5 infection increases the inflammation that follows a single acute exposure to cigarette smoke, by increasing the volume fraction of macrophages and T-lymphocyte helper cells.


Treatment of posttraumatic stress disorder in children and adolescents.
We review recent evidence regarding risk factors for childhood posttraumatic stress disorder (PTSD) and treatment outcome studies from 2010 to 2012 including dissemination studies, early intervention studies and studies involving preschool children. Recent large-scale epidemiological surveys confirm that PTSD occurs in a minority of children and young people exposed to trauma. Detailed follow-up studies of trauma-exposed young people have investigated factors that distinguish those who develop a chronic PTSD from those who do not, with recent studies highlighting the importance of cognitive (thoughts, beliefs and memories) and social factors. Such findings are informative in developing treatments for young people with PTSD. Recent randomized controlled trials (RCTs) confirm that trauma-focused cognitive behaviour therapy (TF-CBT) is a highly efficacious treatment for PTSD, although questions remain about effective treatment components. A small number of dissemination studies indicate that TF-CBT can be effective when delivered in school and community settings. One recent RCT shows that TF-CBT is feasible and highly beneficial for very young preschool children. Studies of early intervention show mixed findings. Various forms of theory-based TF-CBT are highly effective in the treatment of children and adolescents with PTSD. Further work is needed to replicate and extend initial promising outcomes of TF-CBT for very young children. Dissemination studies and early intervention studies show mixed findings and further work is needed.


In situ remediation of hexavalent chromium contaminated soil by CMC-stabilized nanoscale zero-valent iron composited with biochar.
In this study, the remediation experiments were performed outdoors in natural conditions. Carboxymethyl cellulose (CMC)-stabilized nanoscale zero-valent iron (CMC-nZVI), biochar (BC) and CMC-stabilized nanoscale zero-valent iron composited with biochar (CMC-nZVI/BC) were synthesized and investigated for their effect on the in situ remediation of hexavalent chromium [Cr(VI)] contaminated soil and the concentration of available iron was tested after the remediation, compared with the untreated soil. The results of toxicity characteristic leaching procedure (TCLP) test showed that CMC-nZVI and CMC-nZVI/BC used as remediation materials could obviously improve the remediation rate of Cr contaminated soil and when the ratio of CMC-nZVI to Fe0 was 2.5 g/Kg, the leachability of Cr(VI) and Crtotal can be reduced by 100% and 95.8% simultaneously. Moreover, sequential extraction procedure (SEP) showed that most exchangeable Cr converted to carbonate-bound and Fe-Mn oxides-bound, reducing the availability and leachability of Cr in the soil.


Impact of elevated CO₂ and N addition on bacteria, fungi, and archaea in a marsh ecosystem with various types of plants.
The individual effects of either elevated CO2 or N deposition on soil microbial communities have been widely studied, but limited information is available regarding the responses of the bacteria, fungi, and archaea communities to both elevated CO2 and N in wetland ecosystems with different types of plants. Using a terminal restriction fragment length polymorphism (T-RFLP) analysis and real-time quantitative PCR (RT-Q-PCR), we compared communities of bacteria, fungi, and archaea in a marsh microcosm with one of seven macrophytes, Typha latifolia, Phragmites japonica, Miscanthus sacchariflorus, Scirpus lacustris, Juncus effusus, Phragmites australis, or Zizania latifolia, after exposing them to eCO2 and/or amended N for 110 days. Overall, our results showed that the elevated CO2 and N may affect the bacterial and archaeal communities, while they may not affect the fungal community in terms of both diversity and abundance. The effects of elevated CO2 and N on microbial community vary depending on the plant types, and each microbial community shows different responses to the elevated CO2 and N. In particular, elevated CO2 might force a shift in the archaeal community irrespective of the plant type, and the effect of elevated CO2 was enhanced when combined with the N effect. This study indicates that elevated CO2 and N addition could lead to changes in the community structures of bacteria and archaea. Our results also suggest that the fungal group is less sensitive to external changes, while the bacterial and archaeal groups are more sensitive to them. Finally, the characteristics of the plant type and relevant physicochemical factors induced by the elevated CO2 and N may be important key factors structuring the microbial community's response to environmental change, which implies the need for a more comprehensive approach to understanding the pattern of the wetland response to climate change.


BTB-BACK Domain Protein POB1 Suppresses Immune Cell Death by Targeting Ubiquitin E3 ligase PUB17 for Degradation.
Hypersensitive response programmed cell death (HR-PCD) is a critical feature in plant immunity required for pathogen restriction and prevention of disease development. The precise control of this process is paramount to cell survival and an effective immune response. The discovery of new components that function to suppress HR-PCD will be instrumental in understanding the regulation of this fundamental mechanism. Here we report the identification and characterisation of a BTB domain E3 ligase protein, POB1, that functions to suppress HR-PCD triggered by evolutionarily diverse pathogens. Nicotiana benthamiana and tobacco plants with reduced POB1 activity show accelerated HR-PCD whilst those with increased POB1 levels show attenuated HR-PCD. We demonstrate that POB1 dimerization and nuclear localization are vital for its function in HR-PCD suppression. Using protein-protein interaction assays, we identify the Plant U-Box E3 ligase PUB17, a well established positive regulator of plant innate immunity, as a target for POB1-mediated proteasomal degradation. Using confocal imaging and in planta immunoprecipitation assays we show that POB1 interacts with PUB17 in the nucleus and stimulates its degradation. Mutated versions of POB1 that show reduced interaction with PUB17 fail to suppress HR-PCD, indicating that POB1-mediated degradation of PUB17 U-box E3 ligase is an important step for negative regulation of specific immune pathways in plants. Our data reveals a new mechanism for BTB domain proteins in suppressing HR-PCD in plant innate immune responses.


Lidocaine patches reduce pain in trauma patients with rib fractures.
Rib fracture pain is notoriously difficult to manage. The lidocaine patch is effective in other pain scenarios with an excellent safety profile. This study assesses the efficacy of lidocaine patches for treating rib fracture pain. A prospectively gathered cohort of patients with rib fracture was retrospectively analyzed for use of lidocaine patches. Patients treated with lidocaine patches were matched to control subjects treated without patches. Subjective pain reports and narcotic use before and after patch placement, or equivalent time points for control subjects, were gathered from the chart. All patients underwent long-term follow-up, including a McGill Pain Questionnaire (MPQ). Twenty-nine patients with lidocaine patches (LP) and 29 matched control subjects (C) were analyzed. During the 24 hours before patch placement, pain scores and narcotic use were similar (LP 5.3, C 4.6, P = 0.19 and LP 51, C 32 mg morphine, P = 0.17). In the 24 hours after patch placement, LP patients had a greater decrease in pain scores (LP 1.2, C 0.0, P = 0.01) with no change in narcotic use (LP -8.4, C 0.5-mg change in morphine, P = 0.25). At 60 days, LP patients had a lower MPQ pain score (LP 7.7, C 12.2, P < 0.01), although only one patient was still using a patch. There was no difference in time to return to baseline activity (LP 73, C 105 days, P = 0.16) and no adverse events. Lidocaine patches are a safe, effective adjunct for rib fracture pain. Lidocaine patches resulted in a sustained reduction in pain, outlasting the duration of therapy.


Aerobic work capacity in patients with chronic fatigue syndrome.
To determine the aerobic work capacity of patients with the chronic fatigue syndrome and compare it with that of two control groups, and to assess the patients' perception of their level of activity before and during illness. A symptom limited exercise treadmill test with on line gas analysis and blood sampling was used. Subjects were assessed by one investigator, who was blind to the group which they were in. Department of medicine, Royal Victoria Hospital, Belfast. 13 Patients (10 women, three men) who fulfilled the diagnostic criteria for chronic fatigue syndrome. Two control groups of similar age, sex, and body weight: 13 normal subjects (10 women, three men) and seven patients (five women, two men) with the irritable bowel syndrome. Aerobic work capacity as assessed by several variables such as length of time on treadmill, heart rate, and biochemical measurements; Borg score; and visual analogue scores of perceived level of physical activity. The patients with the chronic fatigue syndrome had a reduced exercise capacity compared with that of the other subjects, spending a significantly shorter time on the treadmill. They had a significantly higher heart rate at submaximal levels of exertion and at stage III exertion had significantly higher blood lactate concentrations. Using a Borg score, they showed a significantly altered perception of their degree of physical exertion with a mean score of 8.2 compared with 6.6 and 5.3 for the normal subjects and patients with the irritable bowel syndrome respectively. Using a visual analogue scale they indicated that they had a greater capacity for activity before illness than had the patients with the irritable bowel syndrome, but the scores were not significantly different between the two groups. Both groups of patients indicated reduced activity at the time of testing. Normal controls and patients with the irritable bowel syndrome aspired to a greater level of activity than their current level, but the patients with the chronic fatigue syndrome aspired to a level similar to that which they had had before their illness. Patients with the chronic fatigue syndrome have reduced aerobic work capacity compared with normal subjects and patients with the irritable bowel syndrome. They also have an altered perception of their degree of exertion and their premorbid level of physical activity.


18Fluorodeoxyglucose-positron emission tomography in the management of patients with suspected pancreatic cancer.
To assess the accuracy and clinical impact of 18fluorodeoxyglucose-positron emission tomography (18FDG-PET) on the management of patients with suspected primary or recurrent pancreatic adenocarcinoma, and to assess the utility of 18FDG-PET in grading tumor response to neoadjuvant chemoradiation. The diagnosis, staging, and treatment of pancreatic cancer remain difficult. Small primary tumors and hepatic metastases are often not well visualized by computed tomographic scanning (CT), resulting in a high incidence of nontherapeutic celiotomy and the frequent need for "blind resection." In addition, the distinction between local recurrence and nonspecific postoperative changes after resection can be difficult to ascertain on standard anatomic imaging. 18FDG-PET is a new imaging technique that takes advantage of increased glucose metabolism by tumor cells and may improve the diagnostic accuracy of preoperative studies for pancreatic adenocarcinoma. Eighty-one 18FDG-PET scans were obtained in 70 patients undergoing evaluation for suspected primary or recurrent pancreatic adenocarcinoma. Of this group, 65 underwent evaluation for suspected primary pancreatic cancer. Nine patients underwent 18FDG-PET imaging before and after neoadjuvant chemoradiation, and in eight patients 18FDG-PET scans were performed for possible recurrent adenocarcinoma after resection. The 18FDG-PET images were analyzed visually and semiquantitatively using the standard uptake ratio (SUR). The sensitivity and specificity of 18FDG-PET and CT were determined for evaluation of the preoperative diagnosis of primary pancreatic carcinoma, and the impact of 18FDG-PET on patient management was retrospectively assessed. Among the 65 patients evaluated for primary tumor, 52 had proven pancreatic adenocarcinoma and 13 had benign lesions. 18FDG-PET had a higher sensitivity and specificity than CT in correctly diagnosing pancreatic carcinoma (92% and 85% vs. 65% and 62%). Eighteen patients (28%) had indeterminate or unrecognized pancreatic masses on CT clarified with 18FDG-PET. Seven patients (11%) had indeterminate or unrecognized metastatic disease clarified with 18FDG-PET. Overall, 18FDG-PET suggested potential alterations in clinical management in 28/65 patients (43%) with suspected primary pancreatic adenocarcinoma. Of the nine patients undergoing 18FDG-PET imaging before and after neoadjuvant chemoradiation, four had evidence of tumor regression by PET, three showed stable disease, and two showed tumor progression. CT was unable to detect any response to neoadjuvant therapy in this group. Eight patients had 18FDG-PET scans to evaluate suspected recurrent disease after resection. Four were noted to have new regions of 18FDG-uptake in the resection bed; four had evidence of new hepatic metastases. All proved to have metastatic pancreatic adenocarcinoma. These data confirm that 18FDG-PET is useful in the evaluation of patients with suspected primary or recurrent pancreatic carcinoma. 18FDG-PET is more sensitive and specific than CT in the detection of small primary tumors and in the clarification of hepatic and distant metastases. 18FDG-PET was also of benefit in assessing response to neoadjuvant chemoradiation. Although 18FDG-PET cannot replace CT in defining local tumor resectability, the application of 18FDG-PET in addition to CT may alter clinical management in a significant fraction of patients with suspected pancreatic cancer.


Renal function and rate of hip bone loss in older men: the Osteoporotic Fractures in Men Study.
Older men with reduced renal function are at increased risk of hip bone loss. Given the robustness of this association across different measures and a growing body of literature, our findings indicate that clinicians should take into account renal function when evaluating older men for osteoporosis risk and bone loss. Future randomized controlled trials should test whether interventions in this high risk population are effective in preventing bone loss and decreasing fracture incidence. Studies examining whether kidney impairment, not requiring dialysis, is associated with osteoporosis have reported conflicting results. We tested the hypothesis that reduced renal function in older men as manifested by higher concentrations of cystatin C or lower levels of estimated glomerular filtration rate (eGFR) is associated with higher rates of bone loss. We measured serum cystatin C, serum creatinine and total hip bone mineral density (BMD) at baseline in a cohort of 404 older men enrolled in the Osteoporotic Fractures in Men (MrOS) Study and followed them prospectively for an average of 4.4 years for changes in BMD. Associations between renal function and change in hip BMD were examined using linear regression. In multivariable analysis, the mean rate of decline in total hip BMD showed an increase in magnitude with higher cystatin C concentration (mean annualized percent change -0.29, -0.34, -0.37 and -0.65% for quartiles 1 to 4; p for trend=0.004). Similarly, adjusted rates of hip bone loss were higher among men with lower eGFR as defined by the modification of diet in renal disease formula (mean annualized percent change -0.58, -0.39, -0.37, and -0.31 for quartiles 1 to 4; p for trend=0.02), but not among men with lower eGFR as defined by the Cockcroft-Gault formula (mean annualized percent change -0.47, -0.44, -0.31 and -0.43 for quartiles 1 to 4; p for trend=0.48). Older men with reduced renal function are at increased risk of hip bone loss. Our findings suggest that health care providers should consider renal function when evaluating older men for risk factors for bone loss and osteoporosis.


Assessing the perception of trunk movements in military personnel with chronic non-specific low back pain using a virtual mirror.
Chronic pain, including chronic non-specific low back pain (CNSLBP), is often associated with body perception disturbances, but these have generally been assessed under static conditions. The objective of this study was to use a "virtual mirror" that scaled visual movement feedback to assess body perception during active movement in military personnel with CNSLBP (n = 15) as compared to military healthy control subjects (n = 15). Subjects performed a trunk flexion task while sitting and standing in front of a large screen displaying a full-body virtual mirror-image (avatar) in real-time. Avatar movements were scaled to appear greater, identical, or smaller than the subjects' actual movements. A total of 126 trials with 11 different scaling factors were pseudo-randomized across 6 blocks. After each trial, subjects had to decide whether the avatar's movements were "greater" or "smaller" than their own movements. Based on this two-alternative forced choice paradigm, a psychophysical curve was fitted to the data for each subject, and several metrics were derived from this curve. In addition, task adherence (kinematics) and virtual reality immersion were assessed. Groups displayed a similar ability to discriminate between different levels of movement scaling. Still, subjects with CNSLBP showed an abnormal performance and tended to overestimate their own movements (a right-shifted psychophysical curve). Subjects showed adequate task adherence, and on average virtual reality immersion was reported to be very good. In conclusion, these results extend previous work in patients with CNSLBP, and denote an important relationship between body perception, movement and pain. As such, the assessment of body perception during active movement can offer new avenues for understanding and managing body perception disturbances and abnormal movement patterns in patients with pain.


Mediator kinase module and human tumorigenesis.
Mediator is a conserved multi-subunit signal processor through which regulatory informatiosn conveyed by gene-specific transcription factors is transduced to RNA Polymerase II (Pol II). In humans, MED13, MED12, CDK8 and Cyclin C (CycC) comprise a four-subunit "kinase" module that exists in variable association with a 26-subunit Mediator core. Genetic and biochemical studies have established the Mediator kinase module as a major ingress of developmental and oncogenic signaling through Mediator, and much of its function in signal-dependent gene regulation derives from its resident CDK8 kinase activity. For example, CDK8-targeted substrate phosphorylation impacts transcription factor half-life, Pol II activity and chromatin chemistry and functional status. Recent structural and biochemical studies have revealed a precise network of physical and functional subunit interactions required for proper kinase module activity. Accordingly, pathologic change in this activity through altered expression or mutation of constituent kinase module subunits can have profound consequences for altered signaling and tumor formation. Herein, we review the structural organization, biological function and oncogenic potential of the Mediator kinase module. We focus principally on tumor-associated alterations in kinase module subunits for which mechanistic relationships as opposed to strictly correlative associations are established. These considerations point to an emerging picture of the Mediator kinase module as an oncogenic unit, one in which pathogenic activation/deactivation through component change drives tumor formation through perturbation of signal-dependent gene regulation. It follows that therapeutic strategies to combat CDK8-driven tumors will involve targeted modulation of CDK8 activity or pharmacologic manipulation of dysregulated CDK8-dependent signaling pathways.


The Living Donor Collective: A Scientific Registry for Living Donors.
In the setting of an overall decline in living organ donation and new questions about long-term safety, a better understanding of outcomes after living donation has become imperative. Adequate information on outcomes important to donors may take many years to ascertain and may be evident only by comparing large numbers of donors with suitable controls. Previous studies have been unable to fully answer critical questions, primarily due to lack of appropriate controls, inadequate sample size, and/or follow-up duration that is too short to allow detection of important risks attributable to donation. The Organ Procurement and Transplantation Network does not follow donors long term and has no prospective control group with which to compare postdonation outcomes. There is a need to establish a national living donor registry and to prospectively follow donors over their lifetimes. In addition, there is a need to better understand the reasons many potential donors who volunteer to donate do not donate and whether the reasons are justified. Therefore, the US Health Resources and Services Administration asked the Scientific Registry of Transplant Recipients to establish a national registry to address these important questions. Here, we discuss the efforts, challenges, and opportunities inherent in establishing the Living Donor Collective.


Metabolic syndrome and mental illness.
Patients with mental illnesses such as schizophrenia and bipolar disorder have an increased prevalence of metabolic syndrome and its components, risk factors for cardiovascular disease and type 2 diabetes. Although the prevalence of obesity and other risk factors such as hyperglycemia are increasing in the general population, patients with major mental illnesses have an increased prevalence of overweight and obesity, hyperglycemia, dyslipidemia, hypertension, and smoking, and substantially greater mortality, compared with the general population. Persons with major mental disorders lose 25 to 30 years of potential life in comparison with the general population, primarily due to premature cardiovascular mortality. The causes of increased cardiometabolic risk in this population can include nondisease-related factors such as poverty and reduced access to medical care, as well as adverse metabolic side effects associated with psychotropic medications, such as antipsychotic drugs. Individual antipsychotic medications are associated with well-defined risks of weight gain and related risks for adverse changes in glucose and lipid metabolism. Based on the medical risk profile of persons with major mental illnesses, and the evidence that certain medications can contribute to increased risk, screening and regular monitoring of metabolic parameters such as weight (body mass index), waist circumference, plasma glucose and lipids, and blood pressure are recommended to manage risk in this population. Treatment decisions should incorporate information about medical risk factors in general and cardiometabolic risk in particular. In addition to the implications for individual clinicians, the problem of disparity in meeting healthcare needs for persons with mental illness in comparison with the general population has become an important public policy concern, with recent recommendations from the National Association of State Mental Health Program Directors and the Institute of Medicine. This article provides an overview of cardiometabolic risk in patients with major mental illness and describes steps for risk reduction.


Development and evaluation of orally disintegrating tablets containing the mosapride resin complex.
The purpose of this study was to prepare a mosapride citrate-resin (Amberlite® IRP 88) complex and orally fast-disintegrating tablets of the resin complex. The resinate complex of mosapride-Amberlite® IRP 88, mass ratio 2:1, was prepared in an ethanol-water solution. The effects of alcohol concentration, temperature, and pH of the solution on complex formation were evaluated. The complex physicochemical properties were characterized by differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. Orally disintegrating tablets were prepared by direct compression and were optimized using the response surface method. Optimized orally fast-disintegrating tablets disintegrated within 18 s. The pH dependence of mosapride release from the tablet decreased drug dissolution in simulated saliva, whereas it promptly released in the pH 1.0 solution. The data reported herein clearly demonstrate that tablets containing the mosapride-Amberlite® IRP 88 complex for oral disintegration could be particularly useful for patients with swallowing difficulties.


[Why is my foot swollen and red?].
We present the case of a 26 year old man reporting to the family doctor due to swelling and redness of the foot. After thrombosis and a tumorous mass could be excluded, the suspicion fell on an acrodermatitis chronica atrophican which could be confirmed by laboratory tests. During therapy there was a significant regression of the cutaneous lesion. The treatment of the Lyme disease was taken over by the casualty insurer.


Developing effective strategies for malaria prevention programs for pregnant African women.
The control of malaria in pregnant African women, one of several child survival strategies applied through antenatal care, has been particularly challenging. Prevention and control recommendations for typical areas of high Plasmodium falciparum transmission have promoted the use of antimalarial chemoprophylaxis to prevent placental infection. Persistently low program coverage coupled with diminishing intervention effectiveness have forced a re-evaluation of the relative importance of malaria in pregnancy. The Mangochi Malaria Research Project (MMRP), a prospective evaluation of malaria prevention in pregnant women in rural Malawi conducted during 1987-1990, contributed to establishing new criteria for policy and program development for malaria prevention in pregnancy. The principle findings of the MMRP include: 1) populations at risk of the adverse consequences of malaria in pregnancy include women with low parity, women infected with human immunodeficiency virus, pregnancy during the high malaria transmission season, and the use of a malaria drug that is suboptimally efficacious; 2) the estimated maximum benefits of an antimalarial intervention that clears placental and umbilical cord parasitemia are a 5-12% reduction of low birth weight (LBW), an approximately 35% reduction in the risk of LBW for risks that are actually preventable once a woman has become pregnant (e.g., risks such as infectious disease or poor nutrition during gestation), and a 3-5% reduction in the rate of infant mortality; 3) the intervention must be capable of rendering the woman malaria parasite free, including clearance of parasites from the placental vascular space and umbilical cord blood; 4) other diseases adversely affect pregnancy outcome and, while the control of malaria in pregnancy may not warrant independent programming, if coupled with prevention programs to provide a range of antenatal services, the incremental costs of malaria control may prove to be highly cost-effective; and 5) the choice of a regimen must balance intervention efficacy with safety, availability, affordability, and simplicity of delivery, and several antimalarials may meet these criteria. The Malawi Ministry of Health has modified its malaria prevention in pregnancy recommendations and now faces the challenge of effective programming to improve child survival.


Learned appetites for calcium, phosphorus, and sodium in sheep.
If supplemental minerals are needed to promote optimal animal performance, what is the best way of providing them: free choice or in the diet? We hypothesized that herbivores discriminate among feeds containing Na, P, and Ca and modify their choices as a function of need. One group of lambs was fed a basal diet low in P and high in Ca (low P-high Ca), whereas another group was fed a basal diet high in P and low in Ca (high P-low Ca). After 73 d of exposure to the unbalanced diets, the lambs were conditioned by offering flavored grape pomace containing NaCl, CaCO(3), or NaH(2)PO(4). Preference for pomace + minerals was determined when all lambs were fed a basal diet of alfalfa pellets and barley grain (initial preference) and during 4 phases. Phases 1 and 2 occurred after 40 and 67 d of feeding the unbalanced basal diets, phase 3 occurred after conditioning with NaCl, CaCO(3), or NaH(2)PO(4), and phase 4 occurred 22 d after the groups were moved to 2 new (separate) locations so the animals in the different groups could not eat dirt, urine, or feces from the other pen. Preference for pomace did not differ between the groups during the initial preference tests (P = 0.62); both groups preferred NaCl > CaCO(3) = NaH(2)PO(4) (P < 0.001). As the study progressed, and lambs fed low P-high Ca had lower P and greater Ca concentrations in serum than lambs fed high P-low Ca (P < 0.001), the preference between groups diverged. In phase 2, lambs in high P-low Ca continued to prefer NaCl (P < 0.001), but lambs in low P-high Ca preferred NaH(2)PO(4) (P < 0.05). After conditioning, both groups preferred NaCl = NaH(2)PO(4) > CaCO(3) (P < 0.01 to 0.11). After the groups were moved to different locations, lambs fed low P-high Ca showed the lowest concentration (3.7 mg/dL) of inorganic P in serum for all phases (P < 0.001), and they preferred NaH(2)PO(4) > NaCl = CaCO(3) (P < 0.001). In contrast, lambs in high P-low Ca avoided NaH(2)PO(4) (P < 0.05). Lambs offered high P-low Ca showed a greater preference for CaCO(3) (P = 0.12) and NaCl (P < 0.05) and a lower preference for NaH(2)PO(4) compared with lambs fed low P-high Ca (P < 0.001). In summary, lambs discriminated among different flavored feeds containing NaCl, CaCO(3), and NaH(2)PO(4) and displayed preferences as a function of the mineral imbalance in their basal diets. Thus, it may be possible to feed Ca and P supplements free choice, such that individual animals within a group can manifest preferences based on their specific needs.


Absorption Spectra of FAD Embedded in Cryptochromes.
The magnetic compass sense utilized by migratory birds for long-distance navigation functions only once light of a certain wavelength is present. This piece of evidence fits partially with the popular hypothesis of chemical magnetoreception in cryptochrome proteins, located in the bird retina. According to this hypothesis a magnetosensitive radical pair is produced after photoexcitation of an FAD cofactor inside cryptochrome, and as such the absorption properties of FAD are of crucial importance for cryptochrome activation. However, we reveal that absorption spectra of FAD show very little variation between six different cryptochromes, suggesting that the electronic transitions are barely affected by the chemical differences in the proteins. This conclusion hints on the presence of a secondary photoreceptor or cofactor that could be necessary to explain green-light-activated magnetoreception in birds.


Different patterns of retinal correspondence in the central and peripheral visual field of strabismics.
We tested the state of retinal correspondence at different positions in the visual field of ten observers with strabismic and/or anisometropic amblyopia, four strabismic subjects with alternating fixation and three normal controls. Correspondence was evaluated by the subjective displacement of dichoptic stimuli; to estimate the displacement, we used red-green filters, Bagolini striated glasses, polarizing filters and a phase-difference haploscope. Strabismic observers (amblyopes and alternators) frequently showed variations in the angle of anomaly (ie, the amount of shift of space coordinates in the squinting eye) between different regions of the visual field. Correspondence tended to be closer to normal in the central field and more anomalous in the periphery. These findings cannot be explained by the progressive loss of localization sensitivity with increasing eccentricity. We suggest that the different patterns of retinal correspondence in the central and peripheral visual field of some strabismic observers might be due to a mechanism of selective stabilization of binocular connections in the peripheral visual field, where the larger corresponding areas overcome a limited misalignment of the eyes. In the central visual field, normal correspondence is preserved, and diplopia has to be prevented by interocular suppression.


Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy.
Oral estrogens were the treatment of choice for carcinoma of the prostate for over four decades, but were abandoned because of an excess of cardiovascular and thromboembolic toxicity. It is now recognized that most of this toxicity is related to the first pass portal circulation, which upregulates the hepatic metabolism of hormones, lipids and coagulation proteins. Most of this toxicity can be avoided by parenteral (intramuscular or transdermal) estrogen administration, which avoids hepatic enzyme induction. It also seems that a short-term but modest increase in cardiovascular morbidity (but not mortality) is compensated for by a long-term cardioprotective benefit, which accrues progressively as vascular remodeling develops over time. Parenteral estrogen therapy has the advantage of giving protection against the effects of andropause (similar to the female menopause), which are induced by conventional androgen suppression and include osteoporotic fracture, hot flashes, asthenia and cognitive dysfunction. In addition, parenteral estrogen therapy is significantly cheaper than contemporary endocrine therapy, with substantive economic implications for health providers.


Effect of estrogen on post-heparin lipolytic activity. Selective decline in hepatic triglyceride lipase.
The rise in plasma triglyceride (TG) levels associated with estrogen administration has been thought to arise from impaired clearance because of the uniform suppression of post-heparin lipolytic activity (PHLA). Recently PHLA has been shown to consist of two activities: hepatic TG lipase and extrahepatic lipoprotein lipase (LPL). To determine whether estrogen might induce a selective decline in one of these activities, both hepatic TG lipase and extrahepatic LPL were measured in post-heparin plasma from 13 normal women before and after 2 wk of treatment with ethinyl estradiol (1 mug/kg per day). Hepatic TG lipase and extrahepatic LPL were determined by two techniques: (a) separation by heparin-Sepharose column chromatography, and (b) selective inhibition with specific antibodies to post-heparin hepatic TG lipase and milk LPL. Estrogen uniformly depressed hepatic TG lipase as measured by affinity column (-68 +/- 12%, mean +/- SD, P less than 0.001) or antibody inhibition (-63 +/- 11%, P less than 0.001). Extrahepatic LPL was not significantly changed by affinity column (-22 +/- 40%) or antibody inhibition (-3 +/- 42%). Direct measurement of adipose tissue LPL from buttock fat biopsies also showed no systematic change in the activated form of LPL measured as heparin-elutable LPL (+64 +/- 164%) or in the tissue form of LPL measured in extracts of acetone-ether powders (+21 +/- 77%). The change in hepatic TG lipase correlated with the change in PHLA (r = 0.969, P less than 0.01). However, neither the change in PHLA nor hepatic TG lipase correlated with the increase in TG during estrogen. The decrease in PHLA during estrogen thus results from a selective decline in hepatic TG lipase.


Pulmonary tuberculosis in a South African regional emergency centre: Can infection control be improved to lower the risk of nosocomial transmission?
George Regional Hospital (GRH) is a 272-bed regional referral hospital for the Eden and Central Karoo districts, Western Cape Province, South Africa. The perception among emergency centre (EC) staff is that a high burden of tuberculosis (TB) is being diagnosed and that infection control procedures are currently lacking, leading to a high risk of nosocomial transmission. To establish the burden of pulmonary TB (PTB) presenting to GRH via the EC and audit current infection prevention and control practices, to quantify the risk of transmission of PTB in the EC and to establish whether infection control measures are inadequate. An audit of infection control based on the Centers for Disease Control audit tool for TB, analysis of results, and implementation of new infection control measures including a new standard operating procedure based on a set of triage criteria. Implementation of new triage criteria and a standard operating procedure led to the longest length of stay of a patient with suspected TB in the EC being reduced by 40% (from 142 hours to 84 hours). The average time between seeing a doctor and leaving the EC for patients with suspected TB was reduced by 20% (from 20 hours 40 minutes to 16 hours 45 minutes). Simple measures implemented in the EC led to a significant reduction in the time patients with suspected or confirmed TB spent in the EC. This should lead to a reduced risk of nosocomial transmission of TB to both staff and patients.


Bridging Hospital and Community Care for Homeless Adults with Mental Health Needs: Outcomes of a Brief Interdisciplinary Intervention.
This study examines health and service use outcomes and associated factors among homeless adults participating in a brief interdisciplinary intervention following discharge from hospital. Using a pre-post cohort design, 223 homeless adults with mental health needs were enrolled in the Coordinated Access to Care for the Homeless (CATCH) program, a 4- to 6-month interdisciplinary intervention offering case management, peer support, access to primary psychiatric care, and supplementary community services. Study participants were interviewed at program entry and at 3- and 6-month follow-up visits and assessed for health status, acute care service use, housing outcomes, mental health, substance use, quality of life, and their working alliance with service providers. Linear mixed models and generalized estimating equations were performed to examine outcomes longitudinally. Additional post hoc analyses evaluated differences between CATCH participants and a comparison group of homeless adults experiencing mental illness who received usual services over the same period. In the pre-post analyses, CATCH participants had statistically significant improvements in mental and physical health status and reductions in mental health symptoms, substance misuse, and the number of hospital admissions. The strength of the working alliance between participants and their case manager was associated with reduced health care use and mental health symptoms. Post hoc analyses suggest that CATCH may be associated with statistically significant improvements in mental health symptoms in the study population. A brief interdisciplinary intervention may be a promising approach to improving health outcomes among homeless adults with unmet health needs. Further rigorous research is needed into the effectiveness of brief interventions following discharge from hospital.


Effect of sensory feedback from the proximal upper limb on voluntary isometric finger flexion and extension in hemiparetic stroke subjects.
This study investigated the potential influence of proximal sensory feedback on voluntary distal motor activity in the paretic upper limb of hemiparetic stroke survivors and the potential effect of voluntary distal motor activity on proximal muscle activity. Ten stroke subjects and 10 neurologically intact control subjects performed maximum voluntary isometric flexion and extension, respectively, at the metacarpophalangeal (MCP) joints of the fingers in two static arm postures and under three conditions of electrical stimulation of the arm. The tasks were quantified in terms of maximum MCP torque [MCP flexion (MCP(flex)) or MCP extension (MCP(ext))] and activity of targeted (flexor digitorum superficialis or extensor digitorum communis) and nontargeted upper limb muscles. From a previous study on the MCP stretch reflex poststroke, we expected stroke subjects to exhibit a modulation of voluntary MCP torque production by arm posture and electrical stimulation and increased nontargeted muscle activity. Posture 1 (flexed elbow, neutral shoulder) led to greater MCP(flex) in stroke subjects than posture 2 (extended elbow, flexed shoulder). Electrical stimulation did not influence MCP(flex) or MCP(ext) in either subject group. In stroke subjects, posture 1 led to greater nontargeted upper limb flexor activity during MCP(flex) and to greater elbow flexor and extensor activity during MCP(ext). Stroke subjects exhibited greater elbow flexor activity during MCP(flex) and greater elbow flexor and extensor activity during MCP(ext) than control subjects. The results suggest that static arm posture can modulate voluntary distal motor activity and accompanying muscle activity in the paretic upper limb poststroke.


Filaggrin loss-of-function mutations are not a predisposing factor for atopic dermatitis in an Ishigaki Island under subtropical climate.
Filaggrin (FLG) is a major protein component of the stratum corneum (SC) layer, and FLG loss-of-function mutations are a predisposing factor for atopic dermatitis (AD). Previous cohort studies of children from northern and western Europe have reported FLG loss-of-function mutation frequencies of 15.1-20.9% and 5.8-13.0% in AD and non-AD groups, respectively. To elucidate the association between AD prevalence of FLG loss-of-function mutation carriers and climate conditions, we determined the AD prevalence and FLG loss-of-function mutation frequencies in a cohort of children from Ishigaki Island. Ishigaki Island has a subtropical climate with high humidity (monthly average, 60.8-78.7%) and high temperature (monthly average, 18.5-29.4°C) throughout the year. We diagnosed AD prevalence and analyzed eight FLG loss-of-function mutations in the Japanese population against a cohort of 721 children from the Kyushu University Ishigaki Atopic Dermatitis Study (KIDS) cohort. Parents gave consent for the mutation analysis during their medical examinations from 2001 to 2006. Average AD prevalence was 7.3% per year, and a total of 127 children (17.6%) were diagnosed with AD at least once between 2001 and 2006. The average total serum IgE level differed significantly between the AD and non-AD groups (199.0 and 69.0IU/ml, respectively). Although five kinds of FLG loss-of-function mutations isolated in previous Japanese FLG mutation studies were identified, the FLG loss-of-function mutation frequency in children of the KIDS cohort was not significantly different between the AD and non-AD groups (7.9% and 6.1%, respectively; P=0.174). The FLG loss-of-function mutation frequency was not significantly different between the AD and non-AD groups in a cohort of children from Ishigaki Island, which has a subtropical climate, suggesting that FLG loss-of-function mutations are not always a predisposing factor for AD prevalence.


Enhancement of S1P-induced contractile response in detrusor smooth muscle of rats having cystitis.
Interstitial cystitis is a chronic disease characterized by lower abdominal pain and some nonspecific symptoms including an increase in urinary frequency and urgency. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that controls smooth muscle tone via G-protein coupled receptors (S1P1-3 receptors). S1P production is known to take place both in physiological states and some pathological situations, such as in overactive bladder syndrome. The intracellular mechanism of S1P-induced contractile response was investigated in β-escin permeabilized detrusor smooth muscle of rats having cyclophosphamide-induced cystitis. The bladder was isolated from rats and detrusor smooth muscle strips were permeabilized with β-escin. S1P (50µM)-induced contraction and calcium sensitization response were significantly increased in cystitis. S1P-induced augmented contractile response was inhibited by S1P2 receptor antagonist JTE-013 and S1P3 receptor antagonist suramin. S1P2 receptor protein expressions were increased in cystitis, where no change was observed in S1P3 expressions between control and cystitis groups. S1P-induced contraction was reduced by Rho kinase (ROCK) inhibitor Y-27632 and protein kinase C (PKC) inhibitor GF-109203X in both control and cystitis group. S1P-induced increased calcium sensitization response was decreased by ROCK inhibitor and PKC inhibitor in cystitis. Our findings provide the first evidence that interstitial cystitis triggers S1P-induced increase in intracellular calcium in permeabilized detrusor smooth muscle of female rats. Both S1P2 and S1P3 receptors are involved in S1P mediated enhanced contractile response. The augmentation in S1P-induced contraction in interstitial cystitis involves both PKC and ROCK pathways of calcium sensitization.


Intraobserver and interobserver reliability of visible light spectroscopy during upper gastrointestinal endoscopy.
Visible light spectroscopy (VLS) performed during upper gastrointestinal endoscopy allows measuring mucosal oxygen saturation levels to determine gastrointestinal ischemia. We aimed to determine the observer variability of VLS. This is a single-center prospective study of 24 patients planned for usual care upper endoscopy. To test intraobserver variability, VLS measurements were performed in duplicate by a single endoscopist in 12 patients. For interobserver variability analysis, in another 12 patients VLS measurements were repeatedly and independently performed by two endoscopists in the same patient during the same endoscopy session. Observer variability was assessed with intraclass correlation coefficient (ICC) and clinical disagreement defined as >5% difference between first and second set of VLS measurements. The intraobserver reliability was excellent (ICC antrum 0.77, duodenal bulb 0.81 and duodenum 0.84) with clinical disagreement only in antrum (3% of all intraobserver measurements). The interobserver reliability was good for the duodenal bulb (ICC 0.70) without clinical disagreement; however, interobserver reliability was fair for duodenum (ICC 0.49) and antrum (ICC 0.56) with clinical disagreement occurring in 11% of all interobserver measurements. The observer reliability of VLS is fair to good with intraobserver reliability being better than interobserver reliability. This supports the use of VLS for detection of gastrointestinal ischemia.